TREM2 receptor protects against complement-mediated synaptic loss by binding to complement C1q during neurodegeneration.

Triggering receptor expressed on myeloid cells 2 (TREM2) is strongly linked to Alzheimer's disease (AD) risk, but its functions are not fully understood. Here, we found that TREM2 specifically attenuated the activation of classical complement cascade via high-affinity binding to its initiator C1q. In the human AD brains, the formation of TREM2-C1q complexes was detected, and the increased density of the complexes was associated with lower deposition of C3 but higher amounts of synaptic proteins. In mice expressing mutant human tau, Trem2 haploinsufficiency increased complement-mediated microglial engulfment of synapses and accelerated synaptic loss. Administration of a 41-amino-acid TREM2 peptide, which we identified to be responsible for TREM2 binding to C1q, rescued synaptic impairments in AD mouse models. We thus demonstrate a critical role for microglial TREM2 in restricting complement-mediated synaptic elimination during neurodegeneration, providing mechanistic insights into the protective roles of TREM2 against AD pathogenesis.

Human ApoE2 protects mice against Plasmodium berghei ANKA experimental cerebral malaria.

Cerebral malaria (CM) is a severe neurological complication of Plasmodium falciparum infection with acute brain lesions. Genetic variations in both host and parasite have been associated with susceptibility to CM, but the underlying molecular mechanism remains unclear. Here, we demonstrate that variants of human apolipoprotein E (hApoE) impact the outcome of Plasmodium berghei ANKA (PbA)-induced experimental cerebral malaria (ECM). Mice carrying the hApoE2 isoform have fewer intracerebral hemorrhages and are more resistant to ECM than mice bearing the hApoE3, hApoE4, or endogenous murine ApoE (mApoE). hApoE2 mice infected with PbA showed increased splenomegaly and IFN-γ levels in serum but reduced cerebral cell apoptosis that correlated with the survival advantage against ECM. In addition, upregulated expression of genes associated with lipid metabolism and downregulated expression of genes linked to immune responses were observed in the brain tissue of hApoE2 mice relative to ECM-susceptible mice after PbA infection. Notably, serum cholesterol and the cholesterol content of brain-infiltrating CD8+ T cells are significantly higher in infected hApoE2 mice, which might contribute to a significant reduction in the sequestration of brain CD8+ T cells. Consistent with the finding that fewer brain lesions occurred in infected hApoE2 mice, fewer behavioral deficits were observed in the hApoE2 mice. Finally, a meta-analysis of publicly available data also showed an increased hApoE2 allele in the malaria-endemic African population, suggesting malaria selection. This study shows that hApoE2 protects mice from ECM through suppression of CD8+ T cell activation and migration to the brain and enhanced cholesterol metabolism.IMPORTANCECerebral malaria (CM) is the deadliest complication of malaria infection with an estimated 15%-25% mortality. Even with timely and effective treatment with antimalarial drugs such as quinine and artemisinin derivatives, survivors of CM may suffer long-term cognitive and neurological impairment. Here, we show that human apolipoprotein E variant 2 (hApoE2) protects mice from experimental CM (ECM) via suppression of CD8+ T cell activation and infiltration to the brain, enhanced cholesterol metabolism, and increased IFN-γ production, leading to reduced endothelial cell apoptosis, BBB disruption, and ECM symptoms. Our results suggest that hApoE can be an important factor for risk assessment and treatment of CM in humans.

Self-assembly of multifunctional hydrogels with polyoxometalates helical arrays using nematic peptide liquid crystal template.

In this work, we report a strategy to self-assemble multifunctional hydrogels composed of highly ordered polyoxometalates (POMs) helical arrays using a liquid crystalline tripeptide as the template. The cationic peptide can self-assemble into long-range ordered nanofilaments with a diameter of ~4.1 nm in aqueous media. Through the incorporation of various multivalent polyoxometalates (POMs), the POMs clusters can spontaneously organize into periodic nanowire arrays by the colloidal co-assembly with the as-prepared nematic peptide nanofilaments. This leads to the formation of hybrid gels with tunable mechanical strength by simply changing the charge number of the POMs. The H3PW12O40 (noted as PW) clusters@peptide hybrid hydrogels show excellent adsorption performance of dyes. Moreover, the long-range aligned PW clusters within the co-assembled fiber bundles exhibit great improvement in the efficiency of photodegradation of dyes, which shows 8.7 times higher than that of the pristine PW clusters in the homogeneous phase. The synergistic effect between the adsorption and catalytic process within the hybrid gels is considered to be responsible for its highly catalytic activity. This work highlights a general pathway upon the well-defined organization of the various components into hybrid materials with superior properties using simple peptide liquid crystals as templates.

Role of molecular chirality and solvents in directing the self-assembly of peptide into an ultra-pH-sensitive hydrogel.

We report the self-assembly of an ultra-pH-sensitive hydrogel from a simple dipeptide derivative, ferrocene-diphenylalanine (noted as Fc-FF). The pure Fc-L-Phe-L-Phe-OH (noted as (L)-Fc-FF) or Fc-D-Phe-D-Phe-OH (noted as (D)-Fc-FF) peptide could self-assemble into right- or left-handed nanohelices in a mixture of water and organic solvent leading to formation of stable chiral hydrogels at a very narrow pH range of 5.7-5.9. Intriguingly, if we used a racemic mixture (noted as (L,D)-Fc-FF) of (L)-Fc-FF and (D)-Fc-FF, stable hydrogels could only be formed at much lower pH values with a weak mechanical property. The results indicated that the molecular chirality has great influence on the gelation of the peptides. Moreover, we investigated the gelation behaviour of the peptides in various solvents. Here the water molecules are essential in directing the chiral self-assembly of Fc-FF into entangled chiral nanostructures, leading to the formation of stimuli-responsive hydrogels. And in the presence of water molecules, a small amount of organic co-solvents also has significant effect on the gelation of Fc-FF peptides. This work demonstrated that the gelation of such a bioorganometallic molecule is very sensitive to the molecular conformation of itself and the self-assembly environment (pH, solvents, etc.), which has potential applications in chemical sensing and biomedicine.

Bioinspired pH-Sensitive Fluorescent Peptidyl Nanoparticles for Cell Imaging.

As an invaluable tool for biomedical research, the green fluorescent proteins (GFPs) make tumor cells, amyloid plaques, and pathogenic bacteria equally visible. Here, inspired by the chromophore of GFPs, we constructed a tyrosine-based peptide that show green luminescence in the aggregation state. Similar to the optical property of GFPs, the tyrosine-based peptidyl nanoparticles are stabilized by intermolecular hydrogen bonding and emit fluorescence when the Tyr residues bear phenolic anions. In addition, the tyrosine-based peptide is cell-permeable and endosome-escaped when conjuncted with the GPGR motif of human immunodeficiency virus and can be used for stable cell imaging due to its excellent photostability, pH-sensitivity and biocompatibility in physiological conditions. The results provide a promising pathway to construct peptidyl bioluminescent agents for biomedical applications.

Aromatic Motifs Dictate Nanohelix Handedness of Tripeptides.

Self-assembly of peptides and amyloid fibrils offers an appealing approach for creating chiral nanostructures, which has promising applications in the fields of biology and materials science. Although numerous self-assembled chiral materials have been designed, the precise control of their twisting tendency and their handedness is still a challenge. Herein, we report the self-assembly of chiral nanostructures with precisely tailored architectures by changing the amino acid sequences of the peptides. We designed a series of self-assembling tripeptides bearing different l-amino acid sequences. The peptide with l-Phe-l-Phe sequence preferred to self-assemble into left-handed nanohelices, while with l-Phe-l-Trp right-handed nanohelices would be formed. Moreover, the diameter of the self-assembled nanohelices could be tailored by changing the terminal amino acids (His, Arg, Ser, Glu, and Asp). Circular dichroism (CD) and molecular dynamics simulations (MDSs) revealed that both of the right- and left-handed nanohelices formed by the tripeptides showed negative Cotton effects in the peptide adsorption region but exhibited nearly opposite CD Cotton effects in the aromatic regions. These results indicated that the handedness of the self-assembled helical nanofibers was not only determined by the chirality of the peptide backbone but also closely related to the aromatic stacking, hydrogen bonding and steric interactions induced by the side chains. The findings deepen our understanding on the chiral self-assembly of peptide and offer opportunities for the creation of highly functional chiral nanomaterials.